The proposed research project will examine the interaction of ethanol and brain monoamines. We shall investigate the mechanism(s) by which ethanol produces its effects on dopaminergic, noradrenergic, and serotonergic neurons, and how these changes could be related to ethanol tolerance, physical dependence and withdrawal. Our interest in the role of ethanol in monoamine metabolism stems from a variety of evidence indicating that these amines play a role in some of the prominent symptoms associated with alcoholism. To examine the significance of the action of ethanol on monoamines, we shall determine which physiological and behavioral effects of ethanol can be attributed to its effects on monoaminergic neurons. We shall investigate whether the effects of ethanol on noradrenergic neurons represent a direct effect, and the role of acetaldehyde. A major aspect of the project will be the elucidation of the mechanism(s) by which ethanol affects monoamines. We shall combine in vitro and in vivo methods to examine the synthesis uptake release, and metabolism of monoamines in tissues from acute and chronic ethanol-treated rats. We shall examine such factors as changes in the activities of enzymes in monoamine metabolism, sensitivity of their receptors, involvement of cyclic nucleotides, interaction and effects of the aldehyde condensation products, effect of the availability of calcium, interaction with other neuronal systems. By correlating biochemical, behavioral, and physiological studies, we shall consider the role of monoamines in the development of tolerance and physical dependence. We shall use a behavioral test we have developed to study the central effects of ethanol. Finally, we shall attempt to elucidate the role monoamines play in the withdrawal syndrome. We shall relate changes in brain monoamines brought about by pharmacological manipulations with the severity of withdrawal. It is hoped that this approach will allow us to postulate a new, inclusive hypothesis for alcoholism and will provide the biochemical basis for the rational management of ethanol withdrawal and possibly physical dependence.